The present invention relates to novel derivatives of a series of substituted pyrimidines, to pharmaceutical compositions which contain them, to methods for their preparation and to their use in therapy, particularly in the treatment of neurodegenerative or other neurological disorders of the central and peripheral systems.
Dementing disorders such as age-related cognitive disorders, e.g., senility or Alzheimer""s disease are medical conditions for which there are currently only limited therapies. Although studies suggest that multiple neurotransmitter systems are involved in senile dementia, a loss of cholinergic neurons and a severe depletion of choline acetyltransferase appear to show the earliest and strongest correlations with functional cognitive impairment [see P. T. Francis, A. M. Palmer, N. R. Sims, D. M. Bowen, A. N. Davison, M. M. Esiri, D. Neary, J. S. Snowden and G. K. Wilcock, Neurochemical Studies of Early-onset Alzheimer""s Disease. N. Engl. J. Med., 313, 7 (1985); R. T. Bartus, R. L. Dean, M. Pontecorvo and C. Flicker, The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions. Ann. N. Y. Acad. Sci., 444, 332 (1985); F. Hefti and L. S. Schneider, Nerve Growth Factor and Alzheimer""s Disease, Clin. Neuropharmacol., 14, S62 (1991)]. Several groups have attempted to stimulate cholinergic activity by blocking the breakdown of acetylcholine with acetylcholine esterase inhibitors or by introducing muscarinic or nicotinic agonists [see R. T. Bartus, R. L. Dean III, B. Beer and A. S. Lippa, The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science, 217, 408 (1982); J. Varghese, I. Lieberburg and E. D. Thorsett, Chapter 21. Alzheimer""s Disease: Current Therapeutic Approaches. Annu. Rep. Med. Chem., 28, 197 (1993)]. The approved drugs Cognex(copyright) and Aricept(copyright) are acetylcholine esterase inhibitors.
Nerve growth factor (NGF) is the best characterized neurotrophic factor that is capable of inducing cell differentiation of neural cells and promoting neurite sprouting. The neurotrophic protein NGF primarily affects cholinergic neurons in the central nervous system and may be necessary for their survival [see F. Hefti and P. A. Lapchak, Pharmacology of Nerve Growth Factor in the Brain. Adv. Pharmacol., 24, 239 (1993)]. NGF is not systemically bioavailable, but if it is injected or infused directly into brain, it prevents neuronal cell loss and restores cognitive function in aged or lesioned rats or monkeys [see W. Fischer, A. Bjorklund, K. Chen and F. H. Gage, NGF Improves Spatial Memory in Aged Rodents as a Function of Age. J. Neurosci.,11, 1889 (1991)]. NGF effects ultimately result in the stimulation of choline acetyltransferase, the enzyme for biosynthesis of acetylcholine and the promotion of neurite growth. Consequently, small molecules that produce neurotrophic or xe2x80x9cnerve growth factor-likexe2x80x9d (NGF-like) properties in mammalian cell cultures have potential for use in the treatment of dementing disorders such as age-related senility or Alzheimer""s disease and other neurodegenerative conditions such as peripheral neuropathies, Parkinson""s, stroke damage, transient ischemic attacks or trauma-head injuries.
There are several reports of small molecules that exhibit various aspects of NGF-like activity. Isaxonine [2-(isopropylamino)pyrimidine] was developed as a neurotrophic pharmaceutical but the clinical application was withdrawn, possibly due to toxicological effects [see Neuropathies peripheriques et a I""isaxonine. Nouv. Presse Med., 11, 1189 (1982); S. Lehmann, C. Quirosa-Guillou, U. Becherer, C. Thal and J.-P. Zanetta, Neurite Outgrowth of Neurons of Rat Dorsal Root Ganglia Induced by New Neurotrophic Substances with Guanidine Group; Neurosci. Lett., 152, 57 (1993)]. Several 2-(piperazino)pyrimidine derivatives were reported to possess NGF-like activity and are being studied further for use in treating CNS degenerative diseases [see A. Awaya, H. Kobayashi, K. Horikomi, S. Tanaka, A. M. Kabir, K. Yokoyama,H. Ohna, K. Kato, T. Kitahara, I. Tomino, S. Isayama and S. Nakamura, Neurotrophic Pyrimidine Heterocyclic Compounds. I. The Newly Synthesized Pyrimidine Compounds Promote Neurite Outgrowth of GOTO and Neuro 2a Neuroblastoma Cell Lines, and Potentiate Nerve Growth Factor (NGF)-lnduced Neurite Sprouting of PC-12 Cells. Biol. Pharm. Bull., 16, 248 (1993)]. AIT-082 (4[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid) is reported to enhance NGF action in cultured PC-12 cells and to restore age-induced working memory deficits in mice [see P. J.. Middlemiss, A. J. Glasky, M. P. Rathbone, E. Werstuik, S. Hindley and J. Gysbers, AIT-082, A Unique Purine Derivative, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC-12 cells. Neuroscience Let., 199, 131 (1995)]. In addition, EP0372934, EP0459819 and U.S. Pat. No. 5,075,305 disclose substituted pyrimidines having NGF-like properties and its possible use in treating CNS degenerative diseases like Alzheimer""s disease as well as peripheral neuropathies or other peripheral nervous system disorders.
We have now discovered a series of substituted pyrimidines that demonstrate NGF-like activity and/or enhancement of NGF activity in PC12 cells. The compounds stimulated both neurite outgrowth and choline acetyltransferase activity in in vitro experiments. Such activities are predictive forcausing increased choline acetyltransferase activity in rat striatum and improving cognitative performance in animal models of age-induced working memory deficits by potentiating the activity of endogenous NGF in the brain. [see P. J.. Middlemiss, A. J. Glasky, M. P. Rathbone, E. Werstuik, S. Hindley and J. Gysbers, AIT-082, A Unique Purine Derivative, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC-12 cells. Neuroscience Let., 199, 131 (1995); A. J. Glasky, C. L. Melchior, B. Pirzadeh, N. Heydari and R. F. Ritzmannn, Effect of AIT-082, a Purine Analog, on Working Memory in Normal and Aged Mice. Pharmacol. Biochem. Behav., 47, 325 (1994); R. Morris, Developments of a Water-maze Procedure for Studying Spatial Learning in the Rat. J. Neurosci. Methods, 11, 47 (1984)].
According to the present invention, there are provided novel compounds of Formula I: 
wherein
W is O, CH2, CH2CH2, OCH2 or CH2CH2CH2;
R1 is NR4R5 wherein R4 and R5 are independently H, C3-11alkenyl, C3-11alkynyl, dihydroxyC3-10alkyl, hydroxyC2-10alkyl, C1-6alkoxy, C6-10aryloxy, C6-10arylC1-6alkoxy, C1-6alkyloxyC2-6alkyl, C1-6alkylthioC2-6alkyl, C1-6alkylaminoC2-6alkyl, (C1-6alkyl)j(C3-9cycloalkyl)(CH2)q (wherein j is 0 or 1 and q is 0-6), (C1-6alkyl)j(C4-9heterocycloalkyl)(CH2)q (wherein j and q are as above) and the heterocyclic ring contains one heteroatom which is O, S or N, oxo(C3-8cycloalkyl)(CH2)q (wherein q is 0-6), hydroxy(CH2)p(C3-8cycloalkyl)(CH2)q (wherein p and q are independently 0-6), or C1-8alkyl (provided that both R4 and R5 are not H or C1-6alkyl); pyrrolidino; 3-oxopiperidino; or 4-oxopiperidino;
wherein C or N atoms may be substituted with one or more substituents selected from the group consisting of:
OH;
oxo
C1-6alkyl;
C2-7alkenyl;
C2-7alkynyl;.
C6-10aryl;
C6-10heteroaryl;
hydroxyC1-6alkyl;
dihydroxyC1-6alkyl;
C1-6alkoxy;
C1-6aryloxy;
C6-10heteroaryloxy;
hydroxyC1-6alkoxy;
C1-6alkoxyC1-6alkyl;
C6-10aryloxyC1-6alkyl;
C6-10heteroaryloxyC1-6alkyl;
C3-8cycloalkyl;
C6-10arylC1-6alkyl;
C6-10heteroarylC1-6alkyl;
C6-10arylC1-6alkoxy;
C6-10heteroarylC1-6alkoxy;
C1-6alkylcarbonylC1-6alkyl;
C6-10arylcarbonylC1-6alkyl;
carboxyC1-6alkyl;
C1-6alkoxycarbonylC1-6alkyl;
C6-10aryloxycarbonylC1-6alkyl;
C6-10arylC1-6alkyloxycarbonylC1-6alkyl;
cyanoC1-6alkyl
C1-6alkylthioC1-6alkyl;
C1-6alkylsulfinylC1-6alkyl;
C1-6alkylsulfonylC1-6alkyl;
C6-10arylthioC1-6alkyl;
C6-10arylsulfinylC1-6alkyl;
C6-10arylsulfonylC1-6alkyl;
C6-10arylC1-4alkylthioC1-6alkyl;
C6-10arylC1-6alkylsulfinylC1-6alkyl;
C6-10arylC1-6alkylsulfonylC1-6alkyl;
C6-10heteroarylthioC1-6alkyl;
C6-10heteroarylsulfinylC1-6alkyl;
C6-10heteroarylsulfonylC1-6alkyl;
aziridino;
azetidino;
pyrrolidino;
piperidino;
heptamethyleneimino;
homopiperazino;
N-substituted homopiperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);
piperazino;
N-substituted piperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10 arylC1-6alkyl or C6-10heteroaryl);
morpholino;
homomorpholine;
thiomorpholino;
aminoC1-6alkyl;
C1-6alkylaminoC1-6alkyl;
di(C1-6alkyl)aminoC1-6alkyl (wherein the alkyl groups may be the same or different);
C6-10arylaminoC1-6alkyl;
C6-10arylC1-6alkylaminoC1-6alkyl;
di(C6-10aryl)aminoC1-6alkyl (wherein the aryl groups may be the same or different);
di(C6-10arylC1-6alkyl)aminoC1-6alkyl (wherein the arylalkyl groups may be the same or different);
R12C(O)C1-6alkyl (wherein R12 is aziridino, azetidino, pyrrolidino, piperidino, heptamethyleneimino, piperazino, homopiperazino, morpholino, homomorpholino, or thiomorpholino);
C(O)R6; C(O)C(O)R6; C(S)R6; S(O)2R6; and C(NR11)R6 (wherein R11 is hydrogen, C1-6alkyl or C6-10aryl and R6 may be H or any of the above listed substituents);
R2 is selected from the group consisting of:
H;
NH2;
R3 is selected from the group consisting of:
H;
OR;
NR9R10 (wherein R9 and R10 may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl);
CF3;
C1-6alkyl;
C6-10aryl;
C6-10arylC1-6alkyl;
CH2OC1-6alkyl; and
C6-10heteroaryl;
X is a C6-10 aryl ring or a C6-10 heteroaryl ring optionally substituted with one or more suitable substituents for an aryl ring, Y, wherein Y is selected from the group consisting of:
halogen;
C1-6alkyl;
C2-7alkenyl;
C2-7alkynyl;
C6-10aryl;
C6-10heteroaryl;
OR;
NR9R10 (wherein R9 and R10 may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl);
NROR;
C(O)NR9R10
C(O)OR;
C(O)R;
NRC(O)NR9R10
NRC(O)R;
NRC(O)OR;
CR(OH)R;
OC(O)R;
S(O)nR wherein R is other than H and n is 0, 1 or 2;
NRS(O)mR wherein R is other than H and m is 1 or 2;
S(O)2NR9R10;
NO2;
CN;
CF3; and
OCF3;
R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl;
and pharmaceutically acceptable esters, amides, salts or solvates thereof.
The present invention includes all enantiomeric and diastereomeric forms of the compounds of Formula I either individually or admixed in any proportion.
The present invention further includes prodrugs and active metabolites of the compounds of Formula I. A prodrug includes any compound which, when administered to a mammal, is converted in whole or in part to a compound of Formula I. An active metabolite is a physiologically active compound which results from the metabolism of a compound of Formula I, or a prodrug thereof, when such compound or prodrug is administered to a mammal.
The compounds of Formula I above and their pharmaceutically acceptable esters, amides, salts or solvates are sometimes hereinafter referred to as xe2x80x9cthe compounds according to the inventionxe2x80x9d.
By xe2x80x9calkylxe2x80x9d is meant straight or branched chain alkyl. The alkyl groups may be optionally substituted with hydroxy, alkoxy, amino or halogen.
By xe2x80x9carylxe2x80x9d is meant an aromatic ring such as phenyl or naphthyl;
By xe2x80x9cheteroarylxe2x80x9d is meant a ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S.
By xe2x80x9chalogenxe2x80x9d is meant F, Cl, Br or I.
Preferred compounds included in the present invention are more particularly defined by the following Formulas IA-IC: 
wherein a and b are 0 or 1, a+b=0 or 1 and most preferably a+b=1; c is 0-2; n is 0-3; R2 and Y are hereinbefore defined; and Q is C2-10alkyl optionally substituted with one or more OH; and pharmaceutically acceptable esters, amides, salts or solvates thereof.
Preferred compounds of Formula I are those wherein W is O or CH2 and X is substituted phenyl; and pharmaceutically acceptable esters, amides, salts or solvates thereof.
More preferred compounds of Formula I are those wherein R1 is 4-hydroxycyclohexylamino, W is O, X is 4-chlorophenyl, and R2 is NH2; and pharmaceutically acceptable esters, amides, salts or solvates thereof.
Specifically preferred compounds of Formula I are:
2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-oxocyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-oxocyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-4-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-4-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-4-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-4-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(2-hydroxyethyl)cyclohexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-4-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-oxocyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-oxocyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(2-hydroxyethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(2-hydroxyethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(2-hydroxyethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(2-hydroxyethyl)cyclopentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclopentylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclopentylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclopentylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclopentylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopropylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclopropylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclopropylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclobutylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclopentylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclohexylmethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxyethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxypropylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxybutylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(5-hydroxypentylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(6-hydroxyhexylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-1-methyl(ethylamino))pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1,1-dimethyl-2-hydroxy(ethylamino))pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxymethyl-2-hydroxy(ethylamino))pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-1-hydroxymethyl-1-methyl(ethylamino))pyrimidine
2-Amino-2-Amino-5-(4-chlorophenoxy)-4-(tris(hydroxymethyl)methylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2,3-dihydroxypropylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3,4-dihydroxybutylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(bis(2-hydroxyethyl)amino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(bis(3-hydroxypropyl)amino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-methoxyethylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-methoxypropylamino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)-6-(trifluoromethyl)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxypyrrolidino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxymethylpyrrolidino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxyethylpyrrolidino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxymethylpyrrolidino)pyrimidine
2-Amino-5-(4-chlorophenoxy)-4-(3-(2-hydroxyethyl)pyrrolidino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(cis-4-hydroxycyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(cis-3-hydroxycyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-4-(hydroxymethyl)cyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclohexylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-3-hydroxycyclopentylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-2-hydroxycyclopentylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclopentylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopentylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopropylmethylamino)pyrimidine
5-(4-Chlorophenoxy)-4-(2-hydroxyethylamino)pyrimidine
5-(4-Ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
5-(2,4-Dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
4-(trans-4-Hydroxycyclohexylamino)-5-(4-trifluoromethylphenoxy)pyrimidine
5-(4-Chloro-2-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2,4-dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chloro-2-methylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-bromophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-trifluoromethylphenoxy)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methylphenoxy)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(2-methylphenoxy))pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-isopropylphenoxy)pyrimidine
2-Amino-5-(4-butylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methoxyphenoxy)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(2-methoxyphenoxy)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-(trifluoromethoxy)phenoxy)pyrimidine
2-Amino-5-(2,3-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2,4-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2,6-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chloro-2-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2-chloro-4-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2-chloro-4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(2,4,6-trichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methylbenzyl)pyrimidine
2-Amino-5-(4-chlorobenzyl)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-trifluoromethylbenzyl)pyrimidine
2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(isopropylbenzyl)pyrimidine
2-Amino-5-(4-chlorobenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(4-bromobenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-4-(4-oxopiperidino)-5-(4-trifluoromethylbenzyl)pyrimidine
2-Amino-5-(4-methylbenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(4-ethylbenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(4-chlorobenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(4-bromobenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-4-(4-oxopiperidino)-5-(3-trifluoromethylbenzyl)pyrimidine
2-Amino-5-(4-methylbenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(4-ethylbenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(2,4-dichlorobenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-bromobenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-trifluoromethylbenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-methylbenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-ethylbenzyl)-4-(4-oxopiperidino)pyrimidine
2-Amino-5-(2,4-dichlorobenzyIl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-bromobenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-trifluoromethylbenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-methylbenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(2-chloro-4-ethylbenzyl)-4-(3-oxopiperidino)pyrimidine
5-Benzyl-4-(trans-4-hydroxycyclohexylamino)pyrimidine
5-(4-Chlorobenzyl)-4-(4-oxopiperidino)pyrimidine
5-(4-Bromobenzyl)-4-(4-oxopiperidino)pyrimidine
4-(4-Oxopiperidino)-5-(4-trifluoromethylbenzyl)pyrimidine
5-(4-Methylbenzyl)-4-(4-oxopiperidino)pyrimidine
5-(4-Ethylbenzyl)-4-(4-oxopiperidino)pyrimidine
5-(4-Chlorobenzyl)-4-(3-oxopiperidino)pyrimidine
5-(4-Bromobenzyl)-4-(3-oxopiperidino)pyrimidine
4-(4-Oxopiperidino)-5-(3-trifluoromethylbenzyl)pyrimidine
5-(4-Methylbenzyl)-4-(3-oxopiperidino)pyrimidine
5-(4-Ethylbenzyl)-4-(3-oxopiperidino)pyrimidine
5-(2,4-Dichlorobenzyl)-4-(4-oxopiperidino)pyrimidine
5-(2-Chloro-4-bromobenzyl)-4-(4-oxopiperidino)pyrimidine
5-(2-Chloro-4-trifluoromethylbenzyl)-4-(4-oxopiperidino)pyrimidine
5-(2-Chloro-4-methylbenzyl)-4-(4-oxopiperidino)pyrimidine
5-(2-Chloro-4-ethylbenzyl)-4-(4-oxopiperidino)pyrimidine
5-(2,4-Dichlorobenzyl)-4-(3-oxopiperidino)pyrimidine
5-(2-Chloro-4-bromobenzyl)-4-(3-oxopiperidino)pyrimidine
5-(2-Chloro-4-trifluoromethylbenzyl)-4-(3-oxopiperidino)pyrimidine
5-(2-Chloro-4-methylbenzyl)-4-(3-oxopiperidino)pyrimidine
5-(2-Chloro-4-ethylbenzyl)-4-(3-oxopiperidino)pyrimidine
2-Amino-5-(4-chlorophenethyl)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
2-Amino-5-(4-chlorobenzyloxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
and pharmaceutically acceptable esters, amides, salts or solvates thereof.
In one aspect of the invention there is provided the compounds according to the invention for use in medical therapy particularly for the treatment of neurodegenerative or neurological disorders of the central or peripheral nervous systems.
Examples of nervous system disorders which may be treated in accordance with the invention include dementing disorders such as age-related senility, senile dementia or Age Related Mental Impairment (ARMI), cerebal ataxia, Parkinson""s disease, Alzheimer""s disease, peripheral neuropathy, cognitive disorders secondary to stroke or trauma and attention-deficit hyperactivity disorder.
In a further aspect of the present invention there is included:
a) A method for the treatment of neurodegenerafive or neurological disorders of the central or peripheral nervous systems which comprises treating the subject e.g., a mammal, such as a human, with a therapeutically effective amount of a compound according to the invention.
b) Use of a compound according to the invention in the manufacture of a medicament for the treatment of any of the above-mentioned disorders.
Examples of pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts. However, salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question.
Preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethansulfonic, p-toluenesulfonic, benzenesulfonic and isethionic acids.
The compounds according to the invention and pharmaceutically acceptable esters, amides, salts or solvates thereof may be employed in combination with other therapeutic agents for the treatment of the above disorders. Examples of such further therapeutic agents include Cognex(copyright), Aricept(copyright) and other agents (e.g., acetylcholine esterase inhibitors, muscarinic or nicotinic receptor agonists, MAO inhibitors) that are effective for the treatment of neurodegenerative or neurological disorders of the central or peripheral nervous systems. The component compounds of such combination therapy may be administered simultaneously in either separate or combined formulations, or at different times, e.g., sequentially such that a combined effect is achieved.
While it is possible for compounds according to the invention to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. The formulations of the present invention comprise a compound of Formula I, as above defined, or a pharmaceutically acceptable ester, amide, salt or solvate thereof, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon, for example, the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well know in the art of pharmacy. All methods include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable ester, amide, salt or solvate thereof (active ingredient) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion, or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacterioistats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophillised) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis, as generally described in Pharmaceutical. Res., 3(6), 318 (1986).
Formulations for rectal administration may be presented as suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example, buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Tablets or other forms of presentation in discrete units may conveniently contain an amount of compound of the Formula I which is effective for each of the above-mentioned indications at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually between 10 mg to 250 mg.
For the above-mentioned conditions and disorders, the compounds of the Formula I are preferably administered orally or by injection (intraparenteral or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration is likely to vary depending on the condition and its severity.
For each of the above-mentioned indications the compounds of the Formula I may be administered orally. The dose range for adult humans is generally from about 10 to 4000 mg/day and preferably from about 100 to 1000 mg/day. It may be advantageous to administer an initial dose of 200 to 2000 mg the first day then a lower dose of 100 to 1000 mg on subsequent days.
For each of the above-mentioned indications, the compounds according to the invention may be administered by injection at a dose of from 30 to 800 mg/kg per day.
The present invention further includes processes for the preparation of compounds of Formula I and esters, amides, salts or solvates thereof.
The compounds of formula (I) and their esters, amides, salts and solvates may be prepared in any manner known in the art for the preparation of compounds of analogous structure, for example, in accordance with the present invention, by those methods hereinafter described.
The compounds, esters, amides, salts and solvates of formula (I) may thus be prepared by a process which comprises:
reacting a compound of formula (II) 
wherein R2, R3, W and X are as hereinbefore defined and Z is a leaving group, with an amine NRxe2x80x2Rxe2x80x3 (wherein Rxe2x80x2 and Rxe2x80x3 are as defined for R1) or a suitable derivative thereof. Suitable leaving groups include halogens such as chlorine. The reaction is carried out in an organic solvent (e.g., ethanol, propanol, N,N-dimethylformamide) at a temperature of approximately 20xc2x0 C. to approximately 120xc2x0 C. The compound of formula (II) may be isolated and purified prior to reaction with an amine NRxe2x80x2Rxe2x80x3 or may be used in situ.
Compounds of formula (II) wherein Z is a halogen atom can be prepared from compounds of formula (III) 
wherein R2, R3, W and X are as hereinbefore defined by reaction with a halogenating agent (e.g., Vilsmeier reagent (e.g., oxalyl chloride and N,N-dimethylformamide, oxalyl chloride and N,N-diisopropylformamide), phosphorous oxychloride, phosphorous pentachloride, thionyl chloride) in a suitable organic solvent (e.g., dichloromethane, 1,2-dichlorethane, toluene, N,N-dimethlyformamide) at a temperature of approximately 40xc2x0 C. to approximately 100xc2x0 C.
Compounds of formula (III) can be prepared from compounds of formula (IV) 
wherein R3, W and X are as hereinbefore defined by reaction of an alkaline earth salt of (IV) with formamidine or a derivative of formamidine (e.g., guanidine, thiourea, 2-ethyl-2-thiopseudourea) in a suitable organic solvent (e.g., ethanol, methanol, 2-propanol, tert-butanol, tetrahydrofuran) at a temperature of approximately 60xc2x0 C. to the reflux temperature.
Compounds of formula (IV) can be prepared from compounds of formula (V) 
where in W and X are as hereinbefore defined by reaction with an ester (e.g., ethyl formate, ethyl acetate, ethyl benzoate, ethyl trifluoroacetate) and a strong base (e.g., sodium hydride, potassium hydride, potassium tert-butoxide, sodium metal, lithium diisopropylamine) in a suitable organic solvent (e.g., tetrahydrofuran, ether, toluene) at a temperature of approximately 0xc2x0 C. to approximately 40xc2x0 C.
Compounds of formula (V) can be prepared by various methods known in the art or are available from commercial sources.
Compounds of formula (III) wherein R2 is H can also be prepared from compounds of formula (VI) 
wherein R3, W and X are as hereinbefore defined by reaction with Raney Ni in a suitable solvent (e.g., ethanol, methanol, 2-methoxyethanol) at a temperature of approximately 60xc2x0 C. to approximately 100xc2x0 C.
Specifically preferred intermediate compounds for synthesis of the above-listed specifically preferred compounds of Formula I are:
5-(Phenoxy)isocytosine
5-(4-Methylphenoxy)isocytosine
5-(4-Chlorophenoxy)isocytosine
5-(4-Chlorophenoxy)-2-(mercapto)pyrimidin-4(3H)-one
5-(4-Chlorobenzyl)isocytosine
5-(4-Methylbenzyl)isocytosine
5-(4-Chlorophenoxy)pyrimidin-4(3H)-one
5-(4-Ethylphenoxy)isocytosine
5-(4-Chloro-2-fluorophenoxy)isocytosine
5-(2,4-Dichlorophenoxy)isocytosine
5-(4-Bromophenoxy)isocytosine
5-(4-Trifluoromethylphenoxy)isocytosine
5-(2,4-Difluorophenoxy)isocytosine
5-(3,4-Difluorophenoxy)isocytosine
5-(4-Chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidin-4(3H)-one
5-(4-Chlorophenoxy)-2-(diisopropylaminomethyleneamino)-4-(trans-4-hydroxycyclohexylamino)pyrimidine
4-Chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine
5-(2,4-dichlorobenzyl)isocytosine
5-(2,4,6-trichlorobenzyl)isocytosine
5-(2,4,6-trichlorophenoxy)isocytosine
Esters and amides of compounds of Formula I can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) at a temperature of 0xc2x0 C. to 60xc2x0 C.
Salts of the compounds of Formula I can be made from the free base form by reaction with the appropriate acid.
The following Examples illustrate the present invention but should not be construed as a limitation to the scope thereof.